A Group-Based, Six-Lesson Healthy Eating Curriculum for Individuals With Serious Mental Illnesses: Development and Implementation.

As part of an intervention tailored to individuals with serious mental illnesses in residential settings that aimed to increase dietary intake of fresh vegetables and fruits, we developed and implemented a nutrition and cooking curriculum. To develop the curriculum, we assembled a Workgroup that consisted of professionals from multiple fields. The Workgroup held weekly discussions before drafting what would become the Workbook. Residential staff at partnering housing agencies taught the curriculum to residents. The curriculum Workbook contains six lessons, which are organized around two field trips to a mobile farmers market and a grocery store, and four cooking methods. The Workbook also includes instructions on using FreshConnect Checks at mobile farmers markets. The new curriculum distinguishes itself from other nutrition and culinary literacy curricula in that it delivers knowledge about fresh produce and skills in preparing fruits and vegetables in a way that is tailored to individuals with serious mental illnesses.

State-dependent entrainment of cerebellar nuclear neurons to the local field potential during voluntary movements.

Understanding the relationship between the local field potential (LFP) and single neurons is essential if we are to understand network dynamics and the entrainment of neuronal activity. Here, we investigated the interaction between the LFP and single neurons recorded in the rat cerebellar nuclei (CN), which are part of the sensorimotor network, in freely moving rats. During movement, the LFP displayed persistent oscillations in the theta band frequency, whereas CN neurons displayed intermittent oscillations in the same frequency band contingent on the instantaneous LFP power; the neurons oscillated primarily when the concurrent LFP power was either high or low. Quantification of the relative instantaneous frequency and phase locking showed that CN neurons exhibited phase locked rhythmic activity at a frequency similar to that of the LFP or at a shifted frequency during high and low LFP power, respectively. We suggest that this nonlinear interaction between cerebellar neurons and the LFP power, which occurs solely during movement, contributes to the shaping of cerebellar output patterns.NEW & NOTEWORTHY We studied the interaction between single neurons and the LFP in the cerebellar nuclei of freely moving rats. We show that during movement, the neurons oscillated in the theta frequency band contingent on the concurrent LFP oscillation power in the same band; the neurons oscillated primarily when the LFP power was either high or low. We are the first to demonstrate a nonlinear, state-dependent entrainment of single neurons to the LFP.

Inducing Defects in 19F-Nanocrystals Provides Paramagnetic-free Relaxation Enhancement for Improved In Vivo Hotspot MRI.

Paramagnetic relaxation enhancement (PRE) is the current strategy of choice for enhancing magnetic resonance imaging (MRI) contrast and for accelerating MRI acquisition schemes. Yet, debates regarding lanthanides' biocompatibility and PRE-effect on MRI signal quantification have raised the need for alternative strategies for relaxation enhancement. Herein, we show an approach for shortening the spin-lattice relaxation time (T1) of fluoride-based nanocrystals (NCs) that are used for in vivo 19F-MRI, by inducing crystal defects in their solid-crystal core. By utilizing a phosphate-based rather than a carboxylate-based capping ligand for the synthesis of CaF2 NCs, we were able to induce grain boundary defects in the NC lattice. The obtained defects led to a 10-fold shorter T1 of the NCs' fluorides. Such paramagnetic-free relaxation enhancement of CaF2 NCs, gained without affecting either their size or their colloidal characteristics, improved 4-fold the obtained 19F-MRI signal-to-noise ratio, allowing their use, in vivo, with enhanced hotspot MRI sensitivity.

Bilateral responses of rat ventral striatum tonically active neurons to unilateral medial forebrain bundle stimulation.

Unilateral medial forebrain bundle (MFB) stimulation is an extremely effective promoter of reinforcement learning irrespective of the conditioned cue's laterality. The effectiveness of unilateral MFB stimulation, which activates the mesolimbic pathway connecting the ventral tegmental area to the ventral striatum (vStr), is surprising considering that these fibers rarely cross to the contralateral hemisphere. Specifically, this type of biased fiber distribution entails the activation of brain structures that are primarily ipsilateral to the stimulated MFB, along with weak to negligible activation of the contralateral structures, thus impeding the formation of a cue-outcome association. To better understand the spread of activation of MFB stimulation across hemispheres, we studied whether unilateral MFB stimulation primarily activates the ipsilateral vStr or the vStr of both hemispheres. We simultaneously recorded neuronal activity in the vStr of both hemispheres in response to several sets of unilateral MFB stimulation in anesthetized and freely moving rats. Unilateral MFB stimulation evoked strong stimulus-dependent activation of vStr tonically active neurons (TANs), presumably the cholinergic interneurons, in both hemispheres. However, the TANs' activation patterns and responsiveness depended on whether the stimulus was delivered ipsilaterally or contralaterally to the recorded neuron. These findings indicate that unilateral MFB stimulation effectively activates the vStr in both hemispheres in a stimulus-dependent manner which may serve as neuronal substrate for the formation of cue-outcome associations during reinforcement learning.

Electrochromic Metallo-Organic Nanoscale Films: Fabrication, Color Range, and Devices.

In this study, we demonstrate a versatile approach for the formation of electrochromic nanoscale assemblies on transparent conductive oxides on both rigid and flexible substrates. Our method is based on the application of alternating spin-coated layers of well-defined metal polypyridyl complexes and a palladium(II) salt to form electrochemically addressable films with a high chromophore density. By varying the central metal ion of the polypyridyl complexes (Os, Ru, and Fe) and their ligands and by mixing these complexes, coatings with a wide range of colors can be achieved. These coatings cover a large area of RGB color space. The coloration intensities of these nanoscale films can be tuned by the number of deposition steps. The materials have very attractive ON/OFF ratios, electrochemical stabilities, and coloration efficiencies. Reversible color-to-colorless and color-to-color transitions were demonstrated, and the films were further integrated into sandwich cells.

Rational confederation of genes and diseases: NGS interpretation via GeneCards, MalaCards and VarElect.

BACKGROUND: A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant-harboring genes are associated with a patient's disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include GeneCards (human genes), MalaCards (human diseases) and PathCards (human pathways) together with additional tools, are presented with the focus on MalaCards utility for NGS interpretation as well as for large scale bioinformatic analyses. RESULTS: VarElect, our NGS interpretation tool, leverages the broad information in the GeneCards suite databases. MalaCards algorithms unify disease-related terms and annotations from 69 sources. Further, MalaCards defines hierarchical relatedness-aliases, disease families, a related diseases network, categories and ontological classifications. GeneCards and MalaCards delineate and share a multi-tiered, scored gene-disease network, with stringency levels, including the definition of elite status-high quality gene-disease pairs, coming from manually curated trustworthy sources, that includes 4500 genes for 8000 diseases. This unique resource is key to NGS interpretation by VarElect. VarElect, a comprehensive search tool that helps infer both direct and indirect links between genes and user-supplied disease/phenotype terms, is robustly strengthened by the information found in MalaCards. The indirect mode benefits from GeneCards' diverse gene-to-gene relationships, including SuperPaths-integrated biological pathways from 12 information sources. We are currently adding an important information layer in the form of "disease SuperPaths", generated from the gene-disease matrix by an algorithm similar to that previously employed for biological pathway unification. This allows the discovery of novel gene-disease and disease-disease relationships. The advent of whole genome sequencing necessitates capacities to go beyond protein coding genes. GeneCards is highly useful in this respect, as it also addresses 101,976 non-protein-coding RNA genes. In a more recent development, we are currently adding an inclusive map of regulatory elements and their inferred target genes, generated by integration from 4 resources. CONCLUSIONS: MalaCards provides a rich big-data scaffold for in silico biomedical discovery within the gene-disease universe. VarElect, which depends significantly on both GeneCards and MalaCards power, is a potent tool for supporting the interpretation of wet-lab experiments, notably NGS analyses of disease. The GeneCards suite has thus transcended its 2-decade role in biomedical research, maturing into a key player in clinical investigation.

Firing pattern characteristics of tonically active neurons in rat striatum: context dependent or species divergent?

Tonically active neurons (TANs)--presumably, striatal cholinergic interneurons--exert a strong influence on striatal information processing. Primate studies often describe a characteristic TAN response comprising suppressed activity followed by rebound firing that occasionally is preceded by a brief activation. By contrast, studies in behaving rats report pronounced excitation during movement. These differences in firing patterns may be due to variations in behavioral conditions or could stem from the fact that TANs in rodents use different neuronal mechanisms. If similar/different task conditions yield similar/different activity patterns, then the two species may share neuronal mechanisms; however, if similar task conditions yield different activity patterns, then the two species use different neuronal mechanisms. To evaluate these possibilities, we recorded TAN activity in the ventral and dorsolateral striatal regions in rats performing a simple instrumental task similar in concept to one used in primate studies. We demonstrate that TAN activity is substantially influenced by event context; yet, under identical task conditions, primate and rat TANs display similar activity patterns, whereas under different conditions they do not. Our results suggest that the observed differences in firing patterns likely reflect dissimilarities in task attributes rather than species-dependent neuronal mechanisms and call for re-evaluation of the excitatory response in primate research.

Parallel processing of environmental recognition and locomotion in the mouse striatum.

Information processing in behaving animals has been the target of many studies in the striatum; however, its dynamics and complexity remain to a large extent unknown. Here, we chronically recorded neuronal populations in dorsal striatum as mice were exposed to a novel environment, a paradigm which enables the dissociation of locomotion and environmental recognition. The findings indicate that non-overlapping populations of striatal projection neurons-the medium spiny neurons-reliably encode locomotion and environmental identity, whereas two subpopulations of short-spike interneurons encode distinct information: the fast spiking interneurons preferentially encode locomotion whereas the second type of interneurons preferentially encodes environmental identity. The three neuronal subgroups used cell-type specific coding schemes. This study provides evidence for the existence of parallel processing circuits within the sensorimotor region of the striatum.

A deep-learning strategy to identify cell types across species from high-density extracellular recordings.

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but don't reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals, revealing the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetic activation and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep-learning classifier that predicts cell types with greater than 95% accuracy based on waveform, discharge statistics, and layer of the recorded neuron. The classifier's predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across animal species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously-recorded cell types during behavior.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 9: Synthesis, characterization and molecular modeling of pyridinyl isosteres of N-BPE-8-CAC (1), a high affinity ligand for opioid receptors.

Derivatives of the lead compound N-BPE-8-CAC (1) where each CH of the biphenyl group was individually replaced by N were prepared in hopes of identifying high affinity ligands with improved aqueous solubility. Compared to 1, binding affinities of the five possible pyridinyl derivatives for the µ opioid receptor were between threefold lower to fivefold higher with the Ki of the most potent compound being 0.064 nM. Docking of 8-CAC (2) into the unliganded binding site of the mouse µ opioid receptor (pdb: 4DKL) revealed that 8-CAC and ß-FNA (from 4DKL) make nearly identical interactions with the receptor. However, for 1 and the new pyridinyl derivatives 4-8, binding is not tolerated in the 8-CAC binding mode due to the steric constraints of the large N-substituents. Either an alternative binding mode or rearrangement of the protein to accommodate these modifications may account for their high binding affinity.

Chemical suppression of harmaline-induced body tremor yields recovery of pairwise neuronal coherence in cerebellar nuclei neurons.

Neuronal oscillations occur in health and disease; however, their characteristics can differ across conditions. During voluntary movement in freely moving rats, cerebellar nuclei (CN) neurons display intermittent but coherent oscillations in the theta frequency band (4-12 Hz). However, in the rat harmaline model of essential tremor, a disorder attributed to cerebellar malfunction, CN neurons display aberrant oscillations concomitantly with the emergence of body tremor. To identify the oscillation features that may underlie the emergence of body tremor, we analyzed neuronal activity recorded chronically from the rat CN under three conditions: in freely behaving animals, in harmaline-treated animals, and during chemical suppression of the harmaline-induced body tremor. Suppression of body tremor did not restore single neuron firing characteristics such as firing rate, the global and local coefficients of variation, the likelihood of a neuron to fire in bursts or their tendency to oscillate at a variety of dominant frequencies. Similarly, the fraction of simultaneously recorded neuronal pairs oscillating at a similar dominant frequency (<1 Hz deviation) and the mean frequency deviation within pairs remained similar to the harmaline condition. Moreover, the likelihood that pairs of CN neurons would co-oscillate was not only significantly lower than that measured in freely moving animals, but was significantly worse than chance. By contrast, the chemical suppression of body tremor fully restored pairwise neuronal coherence; that is, unlike in the harmaline condition, pairs of neurons that oscillated at the same time and frequency displayed high coherence, as in the controls. We suggest that oscillation coherence in CN neurons is essential for the execution of smooth movement and its loss likely underlies the emergence of body tremor.

Improving Nutrition Security for Individuals With Serious Mental Illnesses: A Partnership of Public and Nonprofit Agencies.

In conjunction with multiple partners (state agencies, nonprofits, a university, and key stakeholders and content experts), the authors are implementing and evaluating an intervention intended to enable individuals with serious mental illnesses living in community residences (i.e., group homes) and supportive housing apartments to-with support from residential staff-access, purchase, prepare, and enjoy healthy, local produce. The three-component intervention makes fresh produce more accessible; improves its affordability; and conveys knowledge and skills related to purchasing, preparing, and eating healthy foods, especially vegetables. The intervention is being evaluated in preparation for possible larger-scale implementation and potential dissemination to other populations experiencing nutrition insecurity.

Long term ophthalmic complications of distal arthrogryposis type 5D.

BACKGROUND: Distal Arthrogryposis type 5D (DA5D) is a rare genetic disease, expressed phenotypically by skeletal and ocular abnormalities. MATERIALS AND METHODS: Two sisters, ages 42 and 46 years old, were ascertained, both diagnosed with arthrogryposis and unusual ophthalmic late expressions of the disease. They were examined and followed up by both ophthalmologists and medical geneticists. Molecular analysis was performed and population screening followed among healthy individuals of the same ethnic background who reside in the same village. RESULTS: The two sisters expressed myogenic ptosis with poor levator palpebrae function, limitation in up gaze, lagophthalmos, refractive errors, corneal scarring and vascularization along with severe distal arthrogryposis. The newly reported features were: significant lower lid retraction, causing inferior scleral show. Sanger sequencing of the coding regions of ECEL1 gene revealed a homozygous deletion of 46 bps. The carrier frequency is 1:24 (4.2% carriers) in the probands' village. CONCLUSIONS: We diagnosed two patients with DA5D carrying a homozygous pathogenic genetic variant previously reported only once. We report the late ophthalmologic manifestations of this rare disorder and emphasize the importance to recognize possible long-term ophthalmic complications. Measures are needed to diagnose this rare disorder at a younger age and to address ophthalmic and orthopedic complications that might be prevented. We revealed the causative genetic variant and a carrier frequency of 1:24 for DA5D, in the probands' village, thus enabling accurate genetic counselling and justifying genetic testing to the residents of this village as a diagnostic and preventive measure.

Ethnoracial Disparities in Rates of Non-Natural Causes of Death After the 2020 COVID-19 Outbreak in New York State.

Introduction: COVID-19 was associated with increases in non-natural cause mortality in the U.S., including deaths due to drug overdose, homicide, and motor vehicle crashes. Initial reports indicated higher rates of non-natural mortality among ethnoracial minority groups. This report aims to clarify these disparities by documenting trends in non-natural mortality across ethnoracial groups during the 2020 COVID-19 surge in New York State. Methods: We report monthly trends in non-natural cause mortality (overall and stratified by ethnoracial status) in New York State from January 2019 through December 2020, which included the COVID-19 onset in March 2020. Results: Total mean monthly unintentional overdose rates per 100,000 increased from 17.45 (before surge: January 2019-February 2020) to 23.19 (after surge: March 2020-December 2020) (mean difference=5.73, 95% CI=3.82, 7.65; p<0.001). Mean monthly homicide death rates increased from 2.34 before surge to 3.55 after surge (mean difference=1.20, 95% CI=0.60, 1.81; p<0.001), with the increase seen primarily in the non-Latinx Black population. Although increasing unintentional overdose death rates before surge equally affected non-Latinx White, Latinx, and non-Latinx Black persons, they remained high for non-Latinx Black persons but dropped for the other 2 groups after the pandemic onset. None of the ethnoracial subgroups showed significant increases in suicide or motor vehicle crash death rates. Conclusions: Non-Latinx Black persons showed disproportionately high and sustained increased rates of unintentional overdose and homicide death rates after the 2020 COVID-19 surge in New York State. Fatality review and death scene investigation research is needed to better understand these disparities.

Disparities in COVID-19-Related Psychological Distress Among Recipients of a State's Public Mental Health Services.

OBJECTIVE: The authors examined changes in perceived anxiety, stress, and mental health symptoms (i.e., psychological distress) reported by recipients of New York State public mental health services during the early months of the COVID-19 pandemic, as well as whether these changes varied by demographic characteristics or pandemic-related socioeconomic challenges. METHODS: A statewide survey of service recipients (N=3,483) was conducted (May 8-June 22, 2020). Descriptive analyses were summarized, and logistic regression was used to evaluate associations between increases in reported psychological distress and age, gender, region of residence, race and ethnicity, socioeconomic challenges, and alcohol or drug use. RESULTS: Fifty-five percent of respondents (N=1,933) reported a slight or moderate increase in COVID-19-related psychological distress, and 15% (N=520) reported a substantial increase. In adjusted models, substantial elevations in psychological distress were associated with identifying as female (AOR=1.83, 95% CI=1.50-2.25), experiencing three or more pandemic-related socioeconomic challenges (AOR=2.41, 95% CI=1.91-3.03), and reporting increased use of alcohol or drugs (AOR=1.81, 95% CI=1.34-2.44). Compared with non-Hispanic/Latinx White service recipients, non-Hispanic/Latinx Black individuals had lower odds of reporting substantially increased psychological distress (AOR=0.59, 95% CI=0.45-0.76), as did non-Hispanic/Latinx Asian-descent individuals (AOR=0.28, 95% CI=0.12-0.64). CONCLUSIONS: In this large sample of recipients of New York State public mental health services, the COVID-19 pandemic's impact on psychological well-being was widespread and varied by gender, race and ethnicity, and socioeconomic vulnerability. These relationships must be considered in ongoing efforts to provide optimal care for this population.

Redefining the structure-activity relationships of 2,6-methano-3-benzazocines. Part 8. High affinity ligands for opioid receptors in the picomolar Ki range: oxygenated N-(2-[1,1'-biphenyl]-4-ylethyl) analogues of 8-CAC.

N-[2-(4'-methoxy[1,1'-biphenyl]-4-yl)ethyl]-8-CAC (1) is a high affinity (K(i)=0.084 nM) ligand for the µ opioid receptor and served as the lead compound for this study. Analogues of 1 were made in hopes of identifying an SAR within a series of oxygenated (distal) phenyl derivatives. A number of new analogues were made having single-digit pM affinity for the µ receptor. The most potent was the 3',4'-methylenedioxy analogue 18 (K(i)=1.6 pM).

Invariant phase structure of olivo-cerebellar oscillations and its putative role in temporal pattern generation.

Complex movements require accurate temporal coordination between their components. The temporal acuity of such coordination has been attributed to an internal clock signal provided by inferior olivary oscillations. However, a clock signal can produce only time intervals that are multiples of the cycle duration. Because olivary oscillations are in the range of 5-10 Hz, they can support intervals of approximately 100-200 ms, significantly longer than intervals suggested by behavioral studies. Here, we provide evidence that by generating nonzero-phase differences, olivary oscillations can support intervals shorter than the cycle period. Chronically implanted multielectrode arrays were used to monitor the activity of the cerebellar cortex in freely moving rats. Harmaline was administered to accentuate the oscillatory properties of the inferior olive. Olivary-induced oscillations were observed on most electrodes with a similar frequency. Most importantly, oscillations in different recording sites retained a constant phase difference that assumed a variety of values in the range of 0-180 degrees, and were maintained across large global changes in the oscillation frequency. The inferior olive may thus underlie not only rhythmic activity and synchronization, but also temporal patterns that require intervals shorter than the cycle duration. The maintenance of phase differences across frequency changes enables the olivo-cerebellar system to replay temporal patterns at different rates without distortion, allowing the execution of tasks at different speeds.

General Designs Reveal Distinct Codes in Protein-Coding and Non-Coding Human DNA.

This study seeks to investigate distinct signatures and codes within different genomic sequence locations of the human genome. The promoter and other non-coding regions contain sites for the binding of biological particles, for processes such as transcription regulation. The specific rules and sequence codes that govern this remain poorly understood. To derive these (codes), the general designs of sequence are investigated. Genomic signatures are a powerful tool for assessing the general designs of sequence, and cross-comparing different genomic regions for their distinct sequence properties. Through these genomic signatures, the relative non-random properties of sequences are also assessed. Furthermore, a binary components analysis is carried out making use of information theory ideas, to study the RY (purine/pyrimidine), WS (weak/strong) and KM (keto/amino) signatures in the sequences. From this comparison, it is possible to identify the relative importance of these properties within the various protein-coding and non-coding genomic locations. The results show that coding DNA has a strongly non-random WS signature, which reflects the genetic code, and the hydrogen-bond base pairing of codon-anti-codon interactions. In contrast, non-coding locations, such as the promoter, contain a distinct genomic signature. A prominent feature throughout non-coding DNA is a highly non-random RY signature, which is very different in nature to coding DNA, and suggests a structural-based RY code. This marks progress towards deciphering the unknown code(s) in non-protein-coding DNA, and a further understanding of the coding DNA. Additionally, it unravels how DNA carries information. These findings have implications for the most fundamental principles of biology, including knowledge of gene regulation, development and disease.

Multidimensional encoding of movement and contextual variables by rat globus pallidus neurons during a novel environment exposure task.

The basal ganglia (BG) play a critical role in a variety of functions that are essential for animal survival. Information from different cortical areas propagates through the BG in anatomically segregated circuits along the parallel direct and indirect pathways. We examined how the globus pallidus (GP), a nucleus within the indirect pathway, encodes input from the motor and cognitive domains. We chronically recorded and analyzed neuronal activity in the GP of male rats engaged in a novel environment exposure task. GP neurons displayed multidimensional responses to movement and contextual information. A model predicting single unit activity required many task-related behavioral variables, thus confirming the multidimensionality of GP neurons. In addition, populations of GP neurons, but not single units, reliably encoded the animals' locomotion speed and the environmental novelty. We posit that the GP independently processes information from different domains, effectively compresses it and collectively conveys it to successive nuclei.

The Impacts of COVID-19 on a Statewide Population With Mental Illness.

OBJECTIVE: This survey examined the experiences of individuals receiving treatment in a large public mental health system during the early months of the COVID-19 pandemic. METHODS: The survey, conducted between May and June 2020, assessed four domains: impacts on mental health, experiences with telehealth, access to care and resources, and sources and adequacy of support. Descriptive analyses were conducted. RESULTS: Of 4,046 respondents, 70% reported increases in their anxiety and stress because of the pandemic. A majority (55%) reported experiencing challenges related to the social determinants of health and functional needs. Most respondents reported that their care went undisrupted, with 92% using telehealth and 90% reporting feeling adequately supported. CONCLUSIONS: The pandemic substantially affected individuals with mental illness, particularly with regard to mental health related to the social determinants of health and functional needs. However, respondents felt that their mental health care was maintained and that they were adequately supported.